Clinical Trial: Short Versus Extended Antibiotic Treatment With a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients With FUO

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Short Versus Extended Antibiotic Treatment With a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients With Fever of Unknown Origin: a Randomized Multicente

Brief Summary: A multicenter open-label non-inferiority randomized clinical trial comparing the safety (non-inferiority) of short antibiotic treatment (72 hours) with an anti-pseudomonal carbapenem with regard to treatment failure in comparison with extended treatment (at least 9 days) of high-risk febrile neutropenia in hematology patients receiving standard antimicrobial prophylaxis.

Detailed Summary:

Episodes of fever are very common in patients undergoing intensive chemotherapy treatment for malignant hematological disease. More than 80% of patients experience one or more episodes of fever after their first cycle of chemotherapy. Only 20-30% of these patients have a clinically documented focus and mostly include infections of skin, intestinal tract and lung, while at most 10-25% of these patients have microbiologically proven bacteremia during these episodes. Patients with malignant hematological diseases and intensive chemotherapy induced neutropenia are extremely prone to overwhelming bacterial infections. Therefore, empirical antibiotic treatment is initiated at the first occurrence of fever, even if no apparent cause for the fever is evident. Most protocols advice treatment with very broad-spectrum antibiotics, mostly anti-pseudomonal carbapenems or fourth generation anti-pseudomonal cephalosporins.

Prolonged continuation of treatment may induce bacterial resistance. In view of the possible emergence of bacterial resistance due to prolonged antibiotic administration, continuation until recovery of neutropenia is suboptimal because it is costly because of longer hospital admissions, higher antibiotics costs and more possible adverse reactions.

Recent observational data (Slobbe et al) has showed that in adult hematological patients with febrile neutropenia, discontinuation of empiric antibacterial therapy after three days can be safe if no infectious etiology can be found, even in cases with persistent fever. However no RCT has hitherto been performed to support this observational data.

This study compares the safety (non-inferiority) of short treatment (72 hours) versus extended treatment (at least 9 days) with an anti-pseudomonal carbapenem for hematology patients
Sponsor: VU University Medical Center

Current Primary Outcome: The percentage of patients with failed treatment [ Time Frame: From randomization until 30 days after the end of neutropenia. ]

Treatment failure is defined as the occurrence of one of the following events after 3x24hours of treatment with a carbapenem.

The patient:

  • A clinically or microbiologically documented carbapenem-sensitive infection during treatment or within 7 days after discontinuation of carbapenem treatment.

  • Recurrence of fever after previous defervescence (tympanic temperature <37.5 °C during 24 hours) during treatment or within 7 days after discontinuation of carbapenem which is not attributable to administration of a blood product or to a drug reaction.

    • In case of clinical doubt if the fever is of infectious etiology, the recurrence of fever will be considered as failure.
  • The occurrence of death, ARDS/respiratory insufficiency, septic shock (systolic blood pressure <90mmHg and oliguria <500mL/day) due to any cause until the end of neutropenia.

NOTE: Fungal, viral or carbapenem-resistant (inherent or acquired) bacterial infections will not be considered as treatment failure.



Original Primary Outcome: The percentage of patients with failed treatment [ Time Frame: From randomization until 30 days after the end of neutropenia. ]

Treatment failure is defined as the occurrence of one of the following events after 3x24hours of treatment with a carbapenem.

The patient:

  1. Has fever at the first day of the end of the neutropenic episode (defined as the first day with neutrophil count >0.5*10^9/L).
  2. Has experienced recurrence of fever after more than 24 hours of defervescence.
  3. Is diagnosed with a clinically or microbiologically documented infection.
  4. Shows signs or symptoms of septic shock (systolic blood pressure <90mmHg unresponsive to fluid resuscitation and/or oliguria <5mL/kg/hour).
  5. Dies between the start of the investigational treatment protocol and recovery of neutropenia.


Current Secondary Outcome:

  • All-cause mortality. [ Time Frame: 1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia ]
  • Infection-related mortality. [ Time Frame: 1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia ]
  • The length of hospitalization in days. [ Time Frame: From admission until discharge, with an estimated average of 4 weeks ]
  • Treatment strategy failure [ Time Frame: after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode ]

    Treatment strategy failure is defined as occurrence of any of the following events after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode:

    1. Any clinically or microbiologically documented infection.
    2. The recurrence of fever after previous defervescence during neutropenia.
    3. Death, septic shock or ARDS/respiratory failure due to any cause
    4. Adverse drug-related events due to a carbapenem requiring (temporary) interruption of treatment, including but not exclusively: liver and kidney dysfunction, convulsion and allergic reactions.
    5. Unexpected re-admission within 30 days after discharge other than for planned chemotherapy or other elective treatment.
    6. Antibiotic or antifungal treatment within 30days after discharge other than standard antibiotic prophylaxis.
  • The total number of febrile episodes during neutropenia. [ Time Frame: From the start of neutropenia (ANC<0.5x10^9) until the end of neutropenia, an expected average of 21 days ]
  • Time to defervescence [ Time Frame: Onset of fever until defervenscence, an expected average of 5 days. ]

    Fever is defined as one single measured tympanic membrane temperature of >38.5°C or a temperature of >38.0°C during 2 subsequent measurements separated by at least 2 hours.

    Defervescence is defined as three times a tympanic membrane temperature <37.5 °C with a minimal measurement interval of at least 8 hours

  • Incidence and prevalence of Clostridium difficile infection [ Time Frame: Onset of fever until 30 days after the end of neutropenia. ]
  • Candida spp. colonization in (surveillance) cultures [ Time Frame: From onset of fever until 30 days after the end of neutropenia. ]
  • Cost of antimicrobial therapy per admission [ Time Frame: From admission until discharge, with an estimated average of 4 weeks ]
  • The percentage of patients with a MASCC-score≥21 and treatment failure (defined as in primary endpoint) [ Time Frame: From the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days. ]
  • The percentage of patients with mucositis and positive blood cultures or short treatment failure. [ Time Frame: From onset of fever until 30 days after end of neutropenia. ]
  • Bacterial resistance in blood cultures and surveillance cultures (including minimal inhibitory concentrations (MIC)). [ Time Frame: All previous cultures and cultures performed until 30 days after the end of neutropenia. ]
  • The incidence and prevalence of fungal, viral, or carbapenem-resistant (inherent/acquired) infections until the end of neutropenia [ Time Frame: om the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days. ]


Original Secondary Outcome:

  • All-cause mortality [ Time Frame: 1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia ]
  • Infection-related mortality [ Time Frame: 1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia ]
  • The length of hospitalization in days [ Time Frame: From admission until discharge, with an estimated average of 4 weeks ]
  • Unexpected re-admission other than for planned chemotherapy or other elective treatment. [ Time Frame: Within 30 days after discharge. ]
  • The recurrence of fever within 24 hours after discontinuation of antibiotic therapy. [ Time Frame: Within 24 hours after discontinuation of antibiotic therapy. ]
  • The total number of febrile episodes during neutropenia [ Time Frame: From the start of neutropenia (ANC<0.5x10^9) until the end of neutropenia, an expected average of 21 days ]
  • Time to defervescence [ Time Frame: Onset of fever until defervenscence, an expected average of 5 days. ]

    Fever is defined as one single measured tympanic membrane temperature of >38.5°C or a temperature of >38.0°C during 2 subsequent measurements separated by at least 2 hours.

    Defervescence is defined as three times a tympanic membrane temperature <37.5 °C with a minimal measurement interval of at least 8 hours

  • Antibiotic or antifungal treatment within 30days after discharge other than standard antibiotic prophylaxis. [ Time Frame: Within 30 days after discharge. ]
  • Incidence and prevalence of Clostridium difficile infection [ Time Frame: Onset of fever until 30 days after the end of neutropenia. ]
  • Incidence and prevalence of liver and kidney dysfunction [ Time Frame: During antibiotic treatment, an expected average of 7 days ]
  • Candida spp. colonization in (surveillance) cultures [ Time Frame: From onset of fever until 30 days after the end of neutropenia. ]
  • Cost of antimicrobial therapy per admission [ Time Frame: From admission until discharge, with an estimated average of 4 weeks ]
  • MASCC-score [ Time Frame: Once at onset of fever ]
  • The percentage of patients with mucositis and positive blood cultures or short treatment failure. [ Time Frame: From onset of fever until 30 days after end of neutropenia. ]
  • Bacterial resistance in blood cultures and surveillance cultures (including minimal inhibitory concentrations (MIC)). [ Time Frame: All previous cultures and cultures performed until 30 days after the end of neutropenia. ]


Information By: VU University Medical Center

Dates:
Date Received: May 19, 2014
Date Started: December 2014
Date Completion: April 2017
Last Updated: December 8, 2015
Last Verified: December 2015